Resectability, Recurrence, and Risk Stratification of Giant Solitary Fibrous Tumors in the Thoracic Cavity.

BACKGROUND: Solitary fibrous tumors (SFTs) are rare mesenchymal tumors most commonly arising from the pleura in the thoracic cavity. The impact of tumor size on risk of recurrence in thoracic SFTs is not well understood. METHODS: A single institution review was performed on all resected thoracic SFTs (1992-2019) with giant SFT defined as ≥ 15 cm. Clinical information, pathologic characteristics, and long-term survival data were collected, and predictors of recurrence and survival were evaluated with regression and Kaplan-Meier analysis. RESULTS: There were 38 thoracic SFTs resected from patients, with the majority of tumors (n = 23, 60.5%) originating from visceral pleura. There were nine (23.7%) giant SFTs with a mean size 20.4 cm (range 17-30 cm). Mean follow-up time was 81.0 months (range 1-261 months), during which 4 of 38 (10.5%) patients experienced a recurrence within the thorax (range 51-178 months). The presence of tumor necrosis (p = 0.021) and ≥ 4 mitoses per high-powered field (p = 0.010) were associated with SFT recurrence on univariate regression. Overall 5-year, 10-year, and 20-year survival was 78.2%, 72.6%, and 42.4%, respectively, and SFT-related mortality occurred in three patients at 83, 180, and 208 months postoperatively. There were no recurrences or SFT-related mortality among patients with giant SFT. CONCLUSION: This study represents one of the largest contemporary single institution reviews of long-term outcomes of giant thoracic SFT. Our data suggest that size is not a risk factor for recurrence in thoracic SFTs and long-term survival is excellent for giant SFTs.

Ponatinib is a potential therapeutic approach for malignant pleural mesothelioma.

PURPOSE: Malignant pleural mesothelioma (MPM) is a rare and deadly malignancy. Current MPM therapies remain inadequate, and outcomes are often disappointing. New meaningful therapeutic approaches are urgently needed. Accumulating evidence indicates that the cAbl pathway promotes various tumor-stimulating processes in MPM. In this study, we sought to determine ponatinib's potential utility, a clinically approved and potent cAbl inhibitor, in MPM treatment. MATERIAL AND METHODS: Four MPM lines (MSTO211H, H28, H2452, H2052) were treated with ponatinib in vitro, and their growth was assessed. Scratch wound assay was used to investigate the ponatinib effect on cell migration. The expression levels of pAbl and its downstream effectors pCrkL, pAKT, and pSTAT5 were characterized. The in vivo ponatinib effect was evaluated in human MPM cells derived tumor model. RESULTS: In all four MPM lines, significant expression levels of phosphorylated cAbl/Arg and pCrkl were observed. Differentially but strongly, ponatinib inhibited the in vitro cell growth and migration of all four MPM line. Western blot analysis showed that the activation of Abl signaling was blocked in the ponatinib-treated MMP lines. In keeping, the cellular levels of pAbl and its downstream effector pCrkL, pAKT, and pSTAT5 were markedly decrease following ponatinib treatment. Moreover, ponatinib treatment amplified the levels of γH2AX in cells denoting increased double-strand DNA breaks levels. Notably, ponatinib treatment reduced in vivo tumor growth and reduced pCrkl and pSTAT5 levels in tumor samples. CONCLUSION: Ponatinib may offer a new therapeutic strategy for MPM patients based on cAbl signaling pathway inhibition.

Improved outcomes and staging in non-small-cell lung cancer guided by a molecular assay.

There remains a critical need for improved staging of non-small-cell lung cancer, as recurrence and mortality due to undetectable metastases at the time of surgery remain high even after complete resection of tumors currently categorized as 'early stage.' A 14-gene quantitative PCR-based expression profile has been extensively validated to better identify patients at high-risk of 5-year mortality after surgical resection than conventional staging - mortality that almost always results from previously undetectable metastases. Furthermore, prospective studies now suggest a predictive benefit in disease-free survival when the assay is used to guide adjuvant chemotherapy decisions in early-stage non-small-cell lung cancer patients.

Lay abstract There is a need for improvement in the way early-stage non-small-cell lung cancers are staged and treated because many patients with 'early-stage' disease suffer high rates of cancer recurrence after surgery. In recent years, a specialized test has been developed to allow better characterization of a tumor's risk of recurrence based on the genes being expressed by tumor cells. Use of this test, in conjunction with standard staging methods, is better able to identify patients at high risk of cancer recurrence after surgery. Evidence suggests that giving chemotherapy to patients at high risk of recurrence after surgery reduces recurrence rates and improves long-term patient survival.

Lung Cancer Staging and Prognosis.

The seventh edition of the non-small cell lung cancer (NSCLC) TNM staging system was developed by the International Association for the Staging of Lung Cancer (IASLC) Lung Cancer Staging Project by a coordinated international effort to develop data-derived TNM classifications with significant survival differences. Based on these TNM groupings, current 5-year survival estimates in NSLCC range from 73 % in stage IA disease to 13 % in stage IV disease. TNM stage remains the most important prognostic factor in predicting recurrence rates and survival times, followed by tumor histologic grade, and patient sex, age, and performance status. Molecular prognostication in lung cancer is an exploding area of research where interest has moved beyond TNM stage and into individualized genetic tumor analysis with immunohistochemistry, microarray, and mutation profiles. However, despite intense research efforts and countless publications, no molecular prognostic marker has been adopted into clinical use since most fail in subsequent cross-validation with few exceptions. The recent interest in immunotherapy for NSCLC has identified new biomarkers with early evidence that suggests that PD-L1 is a predictive marker of a good response to new immunotherapy drugs but a poor prognostic indicator of overall survival. Future prognostication of outcomes in NSCLC will likely be based on a combination of TNM stage and molecular tumor profiling and yield more precise, individualized survival estimates and treatment algorithms.

Hybrid minimally invasive Ivor Lewis esophagectomy after neoadjuvant chemoradiation yields excellent long-term survival outcomes with minimal morbidity.

BACKGROUND: There is a clear survival benefit to neoadjuvant chemoradiation prior to esophagectomy for patients with stages II-III esophageal cancer. A minimally invasive esophagectomy approach may decrease morbidity but is more challenging in a previously radiated field and therefore patients who undergo neoadjuvant chemoradiation may experience more postoperative complications. METHODS: A prospective database of all esophageal cancer patients who underwent attempted hybrid minimally invasive Ivor Lewis esophagectomy was maintained between 2006 and 2015. The clinical characteristics, neoadjuvant treatments, perioperative complications, and survival outcomes were reviewed. RESULTS: Overall 30- and 90-day mortality rates were 0.8% (1/131) and 2.3% (3/131), respectively. The majority of patients 58% (76/131) underwent induction treatment without significant adverse impact on mortality, major complications, or hospital stay. Overall survival at 1, 3, and 5 years was 85.9%, 65.3%, and 53.9%. Five-year survival by pathologic stage was stage I 68.9%, stage II 54.0%, and stage III 29.6%. CONCLUSIONS: The hybrid minimally invasive Ivor Lewis esophagectomy approach results in low perioperative morbidity and mortality and is well tolerated after neoadjuvant chemoradiation. Good long-term overall survival rates likely resulted from combined concurrent neoadjuvant chemoradiation in the majority of patients, which did not impact the ability to safely perform the operation or postoperative complications rates. J. Surg. Oncol. 2016;114:838-847. © 2016 2016 Wiley Periodicals, Inc.

Airway Esophageal Fistula.

Acquired tracheoesophageal fistulas (TEFs) are rare pathologic connections between the trachea and esophagus. Esophageal and tracheal stenting have been increasingly and safely utilized in management of TEFs, but surgical repair remains the most definitive treatment. Surgical approach to treating TEFs depends on its location, but principles include division and closure of the fistula tracts and insertion of a muscle flap in between the repairs to buttress and prevent recurrence. Advances in diagnostic tools, endoscopic and surgical methods, and intensive care have led to significantly improved outcomes in the management of acquired TEFs.

The Proposed Ninth Edition TNM Classification of Lung Cancer.

A universal nomenclature of the anatomic extent of lung cancer has been critical for individual patient care as well as research advances. As progress occurs, new details emerge that need to be included in a refined system that aligns with contemporary clinical management issues. The ninth edition TNM classification of lung cancer, which is scheduled to take effect in January 2025, addresses this need. It is based on a large international database, multidisciplinary input, and extensive statistical analyses. Key features of the ninth edition include validation of the significant changes in the T component introduced in the eighth edition, subdivision of N2 after exploration of fundamentally different ways of categorizing the N component, and further subdivision of the M component. This has led to reordering of the TNM combinations included in stage groups, primarily involving stage groups IIA, IIB, IIIA, and IIIB. This article summarizes the analyses and revisions for the TNM classification of lung cancer to familiarize the broader medical community and facilitate implementation of the ninth edition system.

Gender representation trends in cardiothoracic surgery journal editorial boards.

OBJECTIVE: We aimed to characterize chronologic trends of gender composition of the editorial boards of major cardiothoracic surgery journals in the current era. METHODS: A cross-sectional analysis was performed of gender representation in editorial board members of 2 North American cardiothoracic surgery journals from 2008 to 2023. Member names and roles were collected from available monthly issues. Validated software programming was used to classify gender. The annual proportion of women representation was compared to the thoracic surgery workforce. RESULTS: During the study period, 558 individuals (3641 names) were identified, 14.3% of whom were women. The total number of editorial board women increased for both journals. The proportion of women also increased from 2.5% (3 out of 118) in 2008 to 17.8% (71 out of 399) in 2023 (P < .001), exceeding the percentage of women in the thoracic surgery workforce, which increased from 3.8% in 2007 to 8.3% in 2021 (P < .001). The average duration of participation was longer for men than for women (53.8 vs 44.5 months; P = .01). Women in editorial board senior roles also increased from 3.3% (1 out of 30) in 2008 to 28.6% (42 out of 147) in 2023 (P < .001), almost triple the increase in nondesignated roles from 2.3% (2 out of 88) in 2008 to 11.5% (29 out of 252) in 2023 (P < .001). CONCLUSIONS: In recent years, the appointment of women to the editorial boards of high-impact cardiothoracic surgery journals and senior roles have proportionally exceeded the overall representation of women in cardiothoracic surgery. These findings indicate progress in inclusive efforts and offer insight toward reducing academic gender disparities.

The Evolving Role for Systemic Therapy in Resectable Non-small Cell Lung Cancer.

During the last 2 decades, the understanding of non-small cell lung cancer (NSCLC) has evolved from a purely histologic classification system to a more complex model synthesizing clinical, histologic, and molecular data. Biomarker-driven targeted therapies have been approved by the United States Food and Drug Administration for patients with metastatic NSCLC harboring specific driver alterations in EGFR, HER2, KRAS, BRAF, MET, ALK, ROS1, RET, and NTRK. Novel immuno-oncology agents have contributed to improvements in NSCLC-related survival at the population-level. However, only in recent years has this nuanced understanding of NSCLC permeated into the systemic management of patients with resectable tumors.

Comparative genomics between matched solid and lepidic portions of semi-solid lung adenocarcinomas.

BACKGROUND: Genetic changes that drive the transition from lepidic to invasive cancer development within a radiographic ground glass or semi-solid lung lesion (SSL) are not well understood. Biomarkers to predict the transition to solid, invasive cancer within SSL are needed. METHODS: Patients with surgically resected SSL were identified retrospectively from a surgical database. Clinical characteristics and survival were compared between stage I SSL (n = 65) and solid adenocarcinomas (n = 120) resected during the same time period. Areas of normal lung, in situ lepidic, and invasive solid tumor were microdissected from within the same SSL specimens and next generation sequencing (NGS) and Affymetrix microarray of gene expression were performed. RESULTS: There were more never smokers, Asian patients, and sub-lobar resections among SSL but no difference in 5-year survival between SSL and solid adenocarcinoma. Driver mutations found in both lepidic and solid invasive portion were EGFR (43%), KRAS (21%), and DNMT3A (5%). CEACAM5 was the most upregulated gene found in solid, invasive portions of SSL. Lepidic and invasive solid areas had many similarities in gene expression, however there were some significant differences with the gene SPP1 being a unique biomarker for the invasive component of a SSL. CONCLUSIONS: Common lung cancer driver mutations are present in in situ lepidic as well as invasive solid portions of a SSL, suggesting early development of driver mutations. CEACAM5 and SPP1 emerged as promising biomarkers of invasive potential in semi-solid lesions. Other studies have shown both genes to correlate with poor prognosis in lung cancer and their role in evolution of semi-solid lung lesions warrants further study.

Brief Report: Increasing Prevalence of Ground-Glass Nodules and Semisolid Lung Lesions on Outpatient Chest Computed Tomography Scans.

Introduction: The increased use of cross-sectional imaging frequently identifies a growing number of lung nodules that require follow-up imaging studies and physician consultations. We report here the frequency of finding a ground-glass nodule (GGN) or semisolid lung lesion (SSL) in the past decade within a large academic health system. Methods: A radiology system database review was performed on all outpatient adult chest computed tomography (CT) scans between 2013 and 2022. Radiology reports were searched for the terms "ground-glass nodule," "subsolid," and "semisolid" to identify reports with findings potentially concerning for an adenocarcinoma spectrum lesion. Results: A total of 175,715 chest CT scans were performed between 2013 and 2022, with a steadily increasing number every year from 10,817 in 2013 to 21,916 performed in the year 2022. Identification of GGN or SSL on any outpatient CT increased from 5.9% in 2013 to 9.2% in 2022, representing a total of 2019 GGN or SSL reported on CT scans in 2022. The percentage of CT scans with a GGN or SSL finding increased during the study period in men and women and across all age groups above 50 years old. Conclusions: The total number of CT scans performed and the percentage of chest CT scans with GGN or SSL has more than doubled between 2013 and 2022; currently, 9% of all chest CT scans report a GGN or SSL. Although not all GGN or SSL radiographic findings represent true adenocarcinoma spectrum lesions, they are a growing burden to patients and health systems, and better methods to risk stratify radiographic lesions are needed.

A guide for managing patients with stage I NSCLC: deciding between lobectomy, segmentectomy, wedge, SBRT and ablation-part 1: a guide to decision-making.

Background: Clinical decision-making for patients with stage I lung cancer is complex. It involves multiple options (lobectomy, segmentectomy, wedge, Stereotactic Body Radiotherapy, thermal ablation), weighing multiple outcomes (e.g., short-, intermediate-, long-term) and multiple aspects of each (e.g., magnitude of a difference, the degree of confidence in the evidence, and the applicability to the patient and setting at hand). A structure is needed to summarize the relevant evidence for an individual patient and to identify which outcomes have the greatest impact on the decision-making. Methods: Based on a systematic review from 2000-2021, evidence regarding relevant outcomes was assembled, with attention to aspects of applicability, uncertainty and effect modifiers. A framework was developed to present this information a format that enhances decision-making at the point of care for individual patients. Results: While patients often cross over several boundaries, the evidence fits into categories of healthy patients, compromised patients, and favorable tumors. In healthy patients with typical (i.e., solid spiculated) lung cancers, the impact on long-term outcomes is the major driver of treatment selection. This is only slightly ameliorated in older patients. In compromised patients increasing frailty accentuates short-term differences and diminishes long-term differences especially when considering non-surgical vs. surgical approaches; nuances of patient selection (technical treatment feasibility, anticipated risk of acute toxicity, delayed toxicity, and long-term outcomes) as well as patient values are increasingly influential. Favorable (less-aggressive) tumors generally have good long-term outcomes regardless of the treatment approach. Discussion: A framework is provided that organizes the evidence and identifies the major drivers of decision-making for an individual patient. This facilitates blending available evidence and clinical judgment in a flexible, nuanced manner that enhances individualized clinical care.

A guide for managing patients with stage I NSCLC: deciding between lobectomy, segmentectomy, wedge, SBRT and ablation-part 2: systematic review of evidence regarding resection extent in generally healthy patients.

Background: Clinical decision-making for patients with stage I lung cancer is complex. It involves multiple options (lobectomy, segmentectomy, wedge, stereotactic body radiotherapy, thermal ablation), weighing multiple outcomes (e.g., short-, intermediate-, long-term) and multiple aspects of each (e.g., magnitude of a difference, the degree of confidence in the evidence, and the applicability to the patient and setting at hand). A structure is needed to summarize the relevant evidence for an individual patient and to identify which outcomes have the greatest impact on the decision-making. Methods: A PubMed systematic review from 2000-2021 of outcomes after lobectomy, segmentectomy and wedge resection in generally healthy patients is the focus of this paper. Evidence was abstracted from randomized trials and non-randomized comparisons with at least some adjustment for confounders. The analysis involved careful assessment, including characteristics of patients, settings, residual confounding etc. to expose degrees of uncertainty and applicability to individual patients. Evidence is summarized that provides an at-a-glance overall impression as well as the ability to delve into layers of details of the patients, settings and treatments involved. Results: In healthy patients there is no short-term benefit to sublobar resection vs. lobectomy in randomized and non-randomized comparisons. A detriment in long-term outcomes is demonstrated by adjusted non-randomized comparisons, more marked for wedge than segmentectomy. Quality-of-life data is confounded by the use of video-assisted approaches; evidence suggests the approach has more impact than the resection extent. Differences in pulmonary function tests by resection extent are not clinically meaningful in healthy patients, especially for multi-segmentectomy vs. lobectomy. The margin distance is associated with the risk of recurrence. Conclusions: A systematic, comprehensive summary of evidence regarding resection extent in healthy patients with attention to aspects of applicability, uncertainty and effect modifiers provides a foundation on which to build a framework for individualized clinical decision-making.

A guide for managing patients with stage I NSCLC: deciding between lobectomy, segmentectomy, wedge, SBRT and ablation-part 3: systematic review of evidence regarding surgery in compromised patients or specific tumors.

Background: Clinical decision-making for patients with stage I lung cancer is complex. It involves multiple options [lobectomy, segmentectomy, wedge, stereotactic body radiotherapy (SBRT), thermal ablation], weighing multiple outcomes (e.g., short-, intermediate-, long-term) and multiple aspects of each (e.g., magnitude of a difference, the degree of confidence in the evidence, and the applicability to the patient and setting at hand). A structure is needed to summarize the relevant evidence for an individual patient and to identify which outcomes have the greatest impact on the decision-making. Methods: A PubMed systematic review from 2000-2021 of outcomes after lobectomy, segmentectomy and wedge resection in older patients, patients with limited pulmonary reserve and favorable tumors is the focus of this paper. Evidence was abstracted from randomized trials and non-randomized comparisons (NRCs) with adjustment for confounders. The analysis involved careful assessment, including characteristics of patients, settings, residual confounding etc. to expose degrees of uncertainty and applicability to individual patients. Evidence is summarized that provides an at-a-glance overall impression as well as the ability to delve into layers of details of the patients, settings and treatments involved. Results: In older patients, perioperative mortality is minimally altered by resection extent and only slightly affected by increasing age; sublobar resection may slightly decrease morbidity. Long-term outcomes are worse after lesser resection; the difference is slightly attenuated with increasing age. Reported short-term outcomes are quite acceptable in (selected) patients with severely limited pulmonary reserve, not clearly altered by resection extent but substantially improved by a minimally invasive approach. Quality-of-life (QOL) and impact on pulmonary function hasn't been well studied, but there appears to be little difference by resection extent in older or compromised patients. Patient selection is paramount but not well defined. Ground-glass and screen-detected tumors exhibit favorable long-term outcomes regardless of resection extent; however solid tumors <1 cm are not a reliably favorable group. Conclusions: A systematic, comprehensive summary of evidence regarding resection extent in compromised patients and favorable tumors with attention to aspects of applicability, uncertainty and effect modifiers provides a foundation for a framework for individualized decision-making.

A guide for managing patients with stage I NSCLC: deciding between lobectomy, segmentectomy, wedge, SBRT and ablation-part 4: systematic review of evidence involving SBRT and ablation.

Background: Clinical decision-making for patients with stage I lung cancer is complex. It involves multiple options [lobectomy, segmentectomy, wedge, stereotactic body radiotherapy (SBRT), thermal ablation], weighing multiple outcomes (e.g., short-, intermediate-, long-term) and multiple aspects of each (e.g., magnitude of a difference, the degree of confidence in the evidence, and the applicability to the patient and setting at hand). A structure is needed to summarize the relevant evidence for an individual patient and to identify which outcomes have the greatest impact on the decision-making. Methods: A PubMed systematic review from 2000-2021 of outcomes after SBRT or thermal ablation vs. resection is the focus of this paper. Evidence was abstracted from randomized trials and non-randomized comparisons with at least some adjustment for confounders. The analysis involved careful assessment, including characteristics of patients, settings, residual confounding etc. to expose degrees of uncertainty and applicability to individual patients. Evidence is summarized that provides an at-a-glance overall impression as well as the ability to delve into layers of details of the patients, settings and treatments involved. Results: Short-term outcomes are meaningfully better after SBRT than resection. SBRT doesn't affect quality-of-life (QOL), on average pulmonary function is not altered, but a minority of patients may experience gradual late toxicity. Adjusted non-randomized comparisons demonstrate a clinically relevant detriment in long-term outcomes after SBRT vs. surgery. The short-term benefits of SBRT over surgery are accentuated with increasing age and compromised patients, but the long-term detriment remains. Ablation is associated with a higher rate of complications than SBRT, but there is little intermediate-term impact on quality-of-life or pulmonary function tests. Adjusted comparisons show a meaningful detriment in long-term outcomes after ablation vs. surgery; there is less difference between ablation and SBRT. Conclusions: A systematic, comprehensive summary of evidence regarding Stereotactic Body Radiotherapy or thermal ablation vs. resection with attention to aspects of applicability, uncertainty and effect modifiers provides a foundation for a framework for individualized decision-making.

Molecular Risk Stratification is Independent of EGFR Mutation Status in Identifying Early-Stage Non-Squamous Non-Small Cell Lung Cancer Patients at Risk for Recurrence and Likely to Benefit From Adjuvant Chemotherapy.

BACKGROUND: A clinically-certified gene expression profile improved survival in a cohort of stage I-IIA NSCLC patients by identifying those likely to benefit from adjuvant intervention. EGFR mutation status has not provided this type of predictive risk discrimination in stage IA NSCLC, and overtreatment of low-risk stage IB patients may have limited the overall benefit seen recently in the adjuvant application of a third-generation TKI. We compared EGFR mutation data to molecular risk stratification in a prospective, early-stage cohort. MATERIALS AND METHODS: Two hundred fifty eligible stage I-IIA non-squamous NSCLC patients underwent prospective molecular risk stratification by the 14-gene prognostic assay. Platinum doublet adjuvant chemotherapy (AC) was recommended for molecular high-risk (MHR). Differences in freedom from recurrence (FFR) and disease-free survival (DFS) were evaluated. RESULTS: At 29 months, prospective molecular testing yielded an estimated FFR of 94.6% and 72.4% in low-risk and untreated MHR patients, respectively, and 97.0% among MHR patients receiving AC (P < .001). In contrast, there was no association between EGFR status and recurrence, while molecular risk predicted survival and response to AC within both the EGFR mutation(+) and mutation(-) populations. Sixty-seven percent of EGFR(+) and 49% of EGFR(-) patients were molecular low-risk. CONCLUSION: This prospective study demonstrates the utility of the 14-gene assay independent of EGFR mutation. Basing adjuvant intervention in early-stage NSCLC on EGFR status alone may undertreat up to 51% of EGFR(-) patients likely to benefit from adjuvant intervention, and overtreat as many as 67% of EGFR(+) patients more likely to be free of residual disease.

Surgery for pleural mesothelioma, when it is indicated and why: arguments against surgery for malignant pleural mesothelioma.

Extrapleural pneumonectomy (EPP) and pleurectomy decortication (PD) are radical operations for malignant pleural mesothelioma (MPM) that remain controversial among thoracic surgeons. There is a lack of randomized evidence to support a survival benefit when major surgical resection is included in multi-modality treatment regimens. Current data from retrospective single institution reviews and prospective trials such as the Surgery for Mesothelioma After Radiation Therapy (SMART) trial are limited by biased patient selection to include only the healthiest patients with most limited disease burden. This patient population predictably has relatively longer survival times than patients with inoperable advanced disease. The only randomized trial to date that has objectively evaluated the true benefit of surgical resection was the Mesothelioma and Radical Surgery (MARS) trial which actually showed shorter survival times among patients who underwent EPP compared with those treated medically. Critics of the MARS trial cite a high perioperative mortality rate for driving these results, however a similar trial has never been repeated to refute the MARS trial results. Finally, it is relevant to consider the high mortality and morbidity rates associated with major operations when recommending these interventions to MPM patients. There is a growing body of literature that identifies patients who clearly obtain no benefit from surgery including those with sarcomatoid or biphasic histology, nodal disease, elevated CRP, elevated platelets and advanced age. Surgery in MPM has risks and is of questionable benefit with outcomes data biased by patient selection of those who will have longer overall survival times regardless of treatment.